Secondary and Primary Dystonia

Pathophysiological Differences

Maja Kojovic; Isabel Pareés; Panagiotis Kassavetis; Francisco J. Palomar; Pablo Mir; James T. Teo; Carla Cordivari; John C. Rothwell; Kailash P. Bhatia; Mark J. Edwards


Brain. 2013;136(7):2038-2049. 

In This Article

Abstract and Introduction


Primary dystonia is thought to be a disorder of the basal ganglia because the symptoms resemble those of patients who have anatomical lesions in the same regions of the brain (secondary dystonia). However, these two groups of patients respond differently to therapy suggesting differences in pathophysiological mechanisms. Pathophysiological deficits in primary dystonia are well characterized and include reduced inhibition at many levels of the motor system and increased plasticity, while emerging evidence suggests additional cerebellar deficits. We compared electrophysiological features of primary and secondary dystonia, using transcranial magnetic stimulation of motor cortex and eye blink classical conditioning paradigm, to test whether dystonia symptoms share the same underlying mechanism. Eleven patients with hemidystonia caused by basal ganglia or thalamic lesions were tested over both hemispheres, corresponding to affected and non-affected side and compared with 10 patients with primary segmental dystonia with arm involvement and 10 healthy participants of similar age. We measured resting motor threshold, active motor threshold, input/output curve, short interval intracortical inhibition and cortical silent period. Plasticity was probed using an excitatory paired associative stimulation protocol. In secondary dystonia cerebellar-dependent conditioning was measured using delayed eye blink classical conditioning paradigm and results were compared with the data of patients with primary dystonia obtained previously. We found no difference in motor thresholds, input/output curves or cortical silent period between patients with secondary and primary dystonia or healthy controls. In secondary dystonia short interval intracortical inhibition was reduced on the affected side, whereas it was normal on the non-affected side. Patients with secondary dystonia had a normal response to the plasticity protocol on both the affected and non-affected side and normal eye blink classical conditioning that was not different from healthy participants. In contrast, patients with primary dystonia showed increased cortical plasticity and reduced eye blink classical conditioning. Normal motor cortex plasticity in secondary dystonia demonstrates that abnormally enhanced cortical plasticity is not required for clinical expression of dystonia, and normal eye blink conditioning suggests an absence of functional cerebellar involvement in this form of dystonia. Reduced short interval intracortical inhibition on the side of the lesion may result from abnormal basal ganglia output or may be a consequence of maintaining an abnormal dystonic posture. Dystonia appears to be a motor symptom that can reflect different pathophysiological states triggered by a variety of insults.


Dystonia is a hyperkinetic movement disorder characterized by sustained muscle contraction leading to twisting, repetitive movements and abnormal postures of affected body parts (Fahn, 1988). In the absence of any pathological cause, Marsden et al. (1985) initially proposed that primary dystonia was a basal ganglia disease on the basis that the symptoms closely resembled those of some patients with identified lesions of the basal ganglia or their output pathways (now classified as secondary dystonia). The implication was that similarity of symptoms was caused by a similar underlying pathophysiology. However, primary and secondary dystonias differ in their response to treatment (Neychev et al., 2011); in addition there is emerging evidence that a cerebellar deficit may contribute to symptoms of primary dystonia (Sadnicka et al., 2012). Given the aetiological and clinical heterogeneity of dystonia, the aim of the present study was to test whether primary and secondary forms share a similar pathophysiological mechanism.

Most electrophysiological and neuroimaging studies in dystonia have been conducted on patients with primary dystonia as this is the most common form of the condition (Bressman, 2004). A consistent finding is loss of inhibition at different levels of the CNS, including spinal cord, brainstem and motor cortex (Berardelli et al.,1985; Nakashima et al., 1989; Ridding et al., 1995a). Recent evidence from human studies suggests that abnormally enhanced synaptic plasticity is also an important factor in pathophysiology of primary dystonias (Peterson et al., 2010; Quartarone and Pisani, 2011). Patients with primary focal and primary generalized dystonia have an enhanced response to different plasticity protocols that probe long-term potentiation-like and long-term depression-like synaptic plasticity in motor cortex (Quartarone et al., 2003, 2008; Edwards et al., 2006; Weise et al., 2006; Gilio et al., 2007) or brainstem circuits (Quartarone et al., 2006a). Finally, a range of recent evidence from structural and functional imaging suggests that the cerebellum has some role in primary dystonia. Thus voxel-based morphometric studies have found grey matter changes in the cerebellum of patients with focal dystonias (Draganski et al., 2003; Delmaire et al., 2007; Obermann et al., 2007) whereas functional MRI has revealed changes in movement-related activity (Odergren et al., 1998; Carbon and Eidelberg, 2009) and metabolic profile (Hutchinson et al., 2000). A finding of reduced eye blink classical conditioning in focal dystonias provides electrophysiological evidence of functional cerebellar involvement in primary dystonia (Teo et al., 2009).

Although there are some reports that patients with secondary dystonia may share similar abnormalities in inhibitory networks of the motor system to those observed in primary dystonia (Nakashima et al., 1989; Trompetto et al., 2012), there is no information about plasticity or cerebellar function in this group of individuals. The aim of the present study was to provide a more comprehensive comparison of the underlying pathophysiology in primary and secondary dystonias. The results show that there are distinct differences in physiology, implying that the clinical syndrome of dystonia has more than one physiological phenotype. This would be consistent with the fact that dystonia can have many different causes and can respond quite differently to treatment (Neychev et al., 2011). The conclusion is that dystonia represents one (of many) possible stable state(s) into which the motor system can be pushed through a variety of insults.